Document Detail

All-trans retinoic acid delays the differentiation of primitive hematopoietic precursors (lin-c-kit+Sca-1(+)) while enhancing the terminal maturation of committed granulocyte/monocyte progenitors.
MedLine Citation:
PMID:  10397716     Owner:  NLM     Status:  MEDLINE    
All-trans retinoic acid (ATRA) is a potent inducer of terminal differentiation of malignant promyelocytes, but its effects on more primitive hematopoietic progenitors and stem cells are less clear. In this study, we investigated the effect of ATRA on highly enriched murine hematopoietic precursor cells (lin-c-kit+Sca-1(+)) grown in liquid suspension culture for 28 days. ATRA initially slowed the growth of these hematopoietic precursors but prolonged and markedly enhanced their colony-forming cell production compared with the hematopoietic precursors cultured in its absence. At 7 and 14 days of culture, a substantially greater percentage of cells cultured with ATRA did not express lineage-associated antigens (55.4% at day 7 and 68.6% at day 14) and retained expression of Sca-1 (44.7% at day 7 and 79.9% at day 14) compared with cells grown in its absence (lin- cells: 31.5% at day 7 and 4% at day 14; Sca-1(+): 10.4% at day 7 and 0.7% at day 14). Moreover, a marked inhibition of granulocyte production was observed in cultures continuously incubated with ATRA. Significantly, ATRA markedly prolonged and enhanced the production of transplantable colony-forming unit-spleen (CFU-S) during 14 days of liquid suspension culture. In contrast with its effects on primitive lin-c-kit+Sca-1(+) hematopoietic precursors, ATRA did not exert the same effects on the more committed lin-c-kit+Sca-1(-) progenitor cells. Moreover, the late addition of ATRA (7 days post-culture initiation) to cultures of primitive hematopoietic precursors resulted in a marked decrease in colony-forming cell production in these cultures, which was associated with enhanced granulocyte differentiation. These observations indicate that ATRA has different effects on hematopoietic cells depending on their maturational state, preventing and/or delaying the differentiation of primitive hematopoietic precursors while enhancing the terminal differentiation of committed granulocyte/monocyte progenitors.
L E Purton; I D Bernstein; S J Collins
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Blood     Volume:  94     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  1999 Jul 
Date Detail:
Created Date:  1999-08-05     Completed Date:  1999-08-05     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  483-95     Citation Subset:  AIM; IM    
Clinical Research and Molecular Medicine Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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MeSH Terms
Antigens, Ly / analysis
Calcitriol / pharmacology
Cell Differentiation / drug effects
Cells, Cultured / drug effects
Colony-Forming Units Assay
Granulocytes / cytology*
Hematopoietic Stem Cells / cytology,  drug effects*
Membrane Proteins / analysis
Mice, Inbred C57BL
Monocytes / cytology*
Proto-Oncogene Proteins c-kit / analysis
Specific Pathogen-Free Organisms
Time Factors
Tretinoin / pharmacology*
Grant Support
Reg. No./Substance:
0/Antigens, Ly; 0/Ly6a protein, mouse; 0/Membrane Proteins; 302-79-4/Tretinoin; 32222-06-3/Calcitriol; EC Proteins c-kit

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